N-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine trihydrate, compositions thereof, and methods for its use

ABSTRACT

The trihydrates of beta-alanine of the formulaAre disclosed. Also method of antogonizing glycoprotein IIb/IIIa activity using these compounds is also disclosed.

TECHNICAL FIELD

The present invention relates to processes for the preparation ofβ-alanine derivative. More particularly, it relates to processes for thepreparation of β-alanine derivative which is glycoprotein IIb/IIIaantagonist, inhibitor of blood platelets aggregation and inhibitor ofthe binding of fibrinogen to blood platelets.

BACKGROUND ART

In PCT WO95/08536, the processes for producing β-alanine derivativewhich is useful as glycoprotein IIb/IIIa antagonist and inhibitor ofplatelet aggregation are disclosed.

DISCLOSURE OF INVENTION

The object of the present invention is to provide the producing processby which β-Alanine derivative, shown the following formula [I] or [II]or a salt thereof, can be produced in a good yield.

The present invention provides a process for producing the β-Alaninederivative illustrated in the Processes 1 and 2 as shown below.

wherein

R¹ is amino protective group,

R² is acyl group, and

R³ is protected carboxy.

Among the compounds (I), (II) and (III), some compounds are novel, andsome are known. They can be prepared from the known compounds in aconventional manner in this field of the art or the similar manners tothose disclosed in Preparations and/or Examples mentioned later in thepresent specification.

Suitable salts of the object compound (I) are conventionalpharmaceutically acceptable and non-toxic salts, and include a metalsalt such as an alkali metal salt [e.g. sodium salt, potassium salt,etc.], an alkaline earth metal salt [e.g. calcium salt, magnesium salt,etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N-dibenzylethylenediamine salt, etc.], an organic acid additionsalt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate,methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], aninorganic acid addition salt [e.g. hydrochloride, hydrobromide,hydroiodide, sulfate, phosphate, etc.], a salt with an amino acid [e.g.arginine salt, aspartic acid salt, glutamic acid salt, etc.] and thelike.

In the above and subsequent descriptions of this specification, suitableexamples of the various definitions are explained in detail as follows:

The term “lower” is intended to mean 1 to 6 carbon atom(s), unlessotherwise indicated.

The term “higher” is used to intend a group having 7 to 20 carbon atoms,unless otherwise provided.

The preferable number of the “one or more” in the term “one or moresuitable substituent(s)” may be 1 to 3.

Suitable “protected carboxy” may be carboxy protected by a conventionalprotecting group such as an esterified carboxy group, or the like, andconcrete examples of the ester moiety in said esterified carboxy groupmay be the ones such as lower alkyl ester [e.g. methyl ester, ethylester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,tert-butyl ester, pentyl ester, isopentyl ester, hexyl ester, isohexylester, 1-cyclopropylethyl ester, etc.] which may have suitablesubstituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g.acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester,valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester,1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethylester, hexanoyloxymethyl ester, etc.], lower-alkanesulfonyl(lower)alkylester [e.g. 2-mesylethyl ester, etc.] or mono(or di ortri)halo(lower)alkyl ester [e.g. 2-iodoethyl ester, 2,2,2-trichloroethylester, etc.];

higher alkyl ester [e.g. heptyl ester, octyl ester, 3,5-dimethyloctylester, 3,7-dimethyloctyl ester, nonyl ester, decyl ester, undecyl ester,dodecyl ester, tridecyl ester, tetradecyl ester, pentadecyl ester,hexadecyl ester, heptadecyl ester, octadecyl ester, nonadecyl ester,adamantyl ester, etc.];

lower alkenyl ester [e.g. (C₂-C₆)alkenyl ester (e.g. vinyl ester, allylester, etc.)];

lower alkynyl ester [e.g. (C₂-C₆)alkynyl ester (e.g. ethynyl ester,propynyl ester, etc.)];

ar(lower)alkyl ester which may have one or more suitable substituent(s)[e.g. phenyl(lower)alkyl ester which may have 1 to 4 lower alkoxy,halogen, nitro, hydroxy, lower alkyl, phenyl, or halo(lower)alkyl, (e.g.benzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzylester, phenethyl ester, trityl ester, benzhydryl ester,bis(nethoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester,etc.)];

aryl ester which may have one or more suitable substituent(s) [e.g.phenyl ester which may have 1 to 4 lower alkyl, or halogen, (e.g. phenylester, 4-chlorophenyl ester, tolyl ester, 4-tert-butylphenyl ester,xylyl ester, mesityl ester, cumenyl ester, etc.), indanyl ester, etc.];

cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl(e.g., cyclopentyloxycarbonyloxymethyl ester,cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethylester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1-(or2-)[cyclopentyloxycarbonyloxy]ethyl ester, 1-(or2-)[cyclohexyloxycarbonyloxy]ethyl ester, 1-(or2-)[cycloheptyloxycarbonyloxy]ethyl ester, etc.) etc.];

(5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-(or2-)(5-methyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or2-)(5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or2-)(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; or the like.

Among them, the preferred one may be lower alkyl ester, ar(lower)alkylester, aryl ester which may have one or more suitable substituent(s),cycloalkyloxycarbonyloxy(lower)alkyl ester or loweralkanoyloxy(lower)alkyl ester,

and the more preferred one may be methyl ester, ethyl ester, butylester, pentyl ester, isopentyl ester, isohexyl ester, benzyl ester,phenethyl ester, phenyl ester, indanyl ester, pivaloyloxymethyl ester or1-cyclohexyloxycarbonyloxyethyl ester.

Suitable “amino protective group” may include acyl group as explainedbelow, a conventional protective group such as ar(lower)alkyl which mayhave 1 to 3 suitable substituent(s) (e.g. benzyl, phenethyl,1-phenylethyl, benzhydryl, trityl, etc.),[5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl](lower)alkyl [e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, etc.] or the like; and the like.

Suitable “acyl group” and “acyl” may include aliphatic acyl, aromaticacyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived fromcarboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and thelike.

Suitable example of said “acyl group” may be illustrated as follows:

aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl,propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl,decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl,pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl,icosanoyl, etc.);

lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);

lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl,etc.);

lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl,etc.); or the like;

aromatic acyl such as

aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);

ar(lower)alkanoyl [e.g., phenyl(C₁-C₆)alkanoyl (e.g., phenylacetyl,phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl,phenylhexanoyl, etc.), naphthyl(C₁-C₆)alkanoyl (e.g., naphthylacetyl,naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];

ar(lower)alkenoyl [e.g., phenyl(C₃-C₆)alkenoyl (e.g., phenylpropenoyl,phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl,etc.), naphthyl(C₃-C₆)alkenoyl (e.g., naphthylpropenoyl,naphthylbutenoyl, etc.), etc.);

ar(lower)alkoxycarbonyl [e.g., phenyl(C₁-C₆)alkoxycarbonyl (e.g.,benzyloxycarbonyl, etc.), etc.];

aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);

aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);

arylcarbamoyl (e.g., phenylcarbamoyl, etc.);

arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.);

arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);

arylsulfonyl which may have 1 to 4 lower alkyl (e.g., phenylsulfonyl,p-tolylsulfonyl, etc.); or the like;

heterocyclic acyl such as

heterocycliccarbonyl;

heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl,heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl,heterocyclichexanoyl, etc.);

heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl,heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl,etc.);

heterocyclicglyoxyloyl; or the like; and the like.

Suitable “heterocyclic” moiety in the terms “heterocycliccarbonyl”,“heterocyclic(lower)alkyl”, “heterocyclic(lower)alkenoyl” and“heterocyclicglyoxyloyl” as mentioned above, and “heterocyclic group”mean saturated or unsaturated monocyclic or polycyclic heterocyclicgroup containing at least one hetero-atom such as an oxygen, sulfur,nitrogen atom and the like. Among them, the preferable heterocyclicgroup may be heterocyclic group such as

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,1-H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl,benzimidazolyl, quinolyl, dihydroquinolyl, isoquinolyl, indazolyl,quinoxalinyl, dihydroquinoxalinyl, benzotriazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s), for example,thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.

The acyl moiety as mentioned above may have one to ten, same ordifferent, suitable substituent(s) such as

lower alkyl (e.g., methyl, ethyl, propyl, etc.);

lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.);

lower alkylthio (e.g., methylthio, ethylthio, etc.);

lower alkylamino (e.g., methylamino, ethylamino, propylamino, etc.);

cyclo(lower)alkyl [e.g. cyclo(C₃-C₆)alkyl (e.g. cyclopentyl, cyclohexyl,etc.]);

cyclo(lower)alkenyl [e.g. cyclo(C₃-C₆)alkenyl (e.g., cyclohexenyl,cyclohexadienyl, etc.);

halogen (e.g., fluorine, chlorine, bromine, iodine); amino; aminoprotective group as mentioned above; hydroxy; protected hydroxy asmentioned below; cyano; nitro; carboxy; protected carboxy as mentionedabove; sulfo; sulfamoyl; imino; oxo;

amino(lower)alkyl (e.g., aminomethyl, aminoethyl, etc.); carbamoyloxy;hydroxy(lower)alkyl (e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or3-hydroxypropyl, etc.), or the like.

Suitable “protected hydroxy” may include acyl as mentioned above,phenyl(lower)alkyl which may have one or more suitable substituent(s)(e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl[e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl,etc.), etc.], tetrahydropyranyl and the like.

The more preferred example of “amino protective group” may be loweralkoxycarbonyl or ar(lower)alkoxycarbonyl, and the most preferred onemay be t-butoxycarbonyl or benzyloxycarbonyl.

Suitable “acyl group” of R² can be referred to aforementioned “acylgroup”. Among them, the more preferred one may be lower alkanoyl, andthe most preferred one may be acetyl.

The processes of the present invention are explained in detail in thefollowing.

Process 1

The object compound (I) or a salt thereof can be prepared by subjectinga compound (II) or a salt thereof to elimination reaction of carboxyprotective group, and then the acylation reaction of amino group.

The Elimination Reaction of Carboxy Protective Group

This reaction is carried out in accordance with a conventional methodsuch as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. lithium, sodium, potassium, etc.], an alkalineearth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonateor bicarbonate thereof, trialkylamine [e.g. trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like. Among them, the preferred one may be lithium anhydride.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.]and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].

The elimination using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.] or the like, ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent. The reaction temperature is not critical and thereaction is usually carried out under cooling to warming.

The reduction method applicable for the elimination reaction may includechemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal [e.g. tin, zinc, iron, etc.] or metallic compound[e.g. chromium chloride, chromium acetate, etc.] and an organic orinorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts [e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.], palladium catalysts [e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium, sulfate, palladium on barium carbonate, etc.], nickel catalysts[e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobaltcatalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts[e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reducedcopper, Raney copper, Ulman copper, etc.] and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.Additionally, in case that the above-mentioned acids to be used inchemical reduction are in liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent, and other conventional solvent such as diethylether, dioxane tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming.

The Acylation Reaction of Amino Group

Suitable acylating agent to be used in the present acylation reactionmay include the compound of the formula

R²—OH  (IV)

(wherein R² is acyl as mentioned before) or its reactive derivative, ora salt thereof.

Suitable reactive derivative at the amino group of the compound obtainedby elimination reaction of carboxy protective group mentioned above mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound obtained by elimination reactionof carboxy protective group mentioned above with a carbonyl compoundsuch as aldehyde, ketone or the like; a silyl derivative formed by thereaction of the compound obtained by elimination reaction of carboxyprotective group mentioned above with a silyl compound such asN,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like;a derivative formed by the reaction of the compound obtained byelimination reaction of carboxy protective group mentioned above withphosphorus trichloride or phosgene, and the like.

Suitable reactive derivative of the compound (IV) may include an acidhalide, an acid anhydride (e.g., acetic anhydride, etc.), an activatedester, and the like. Among them, the preferred one may be acidanhydride, and most preferred one may be acetic anhydride. The suitableexample may be an acid chloride; acid azide; a mixed acid anhydride withan acid such as substituted phosphoric acid (e.g., dialkylphosphoricacid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoricacid, halogenated phosphoric acid, etc.), dialkylphosphorous acid,sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g.,methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid,alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid,pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroaceticacid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); asymmetrical acid anhydride; an activated amide with imidazole,4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; anactivated ester (e.g., cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl [(CH₃)₂ ⁺N═CH—] ester, vinyl ester, propargyl ester,p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester,phenylthio ester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.); an ester with a N-hydroxy compound (e.g.,N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide,1-hydroxy-6-chloro-1H-benzotriazole, etc.); and the like. These reactivederivatives can optionally be selected from them accordingly to the kindof the compound obtained by elimination reaction of carboxy protectivegroup mentioned above to be used.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvents which donot adversely affect the reaction, or the mixture thereof.

When the compound obtained by elimination reaction of carboxy protectivegroup mentioned above is used in free acid form or its salt form in thereaction, the reaction is preferably carried out in the presence of aconventional condensing agent such as N,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;N,N-carbonyl-bis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate;phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride;thionyl chloride; oxalyl chloride; triphenylphosphite;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an organic orinorganic base such as an alkali metal, bicarbonate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine,N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to heating.

Process 2

The object compound (III) or a salt thereof can be prepared bysubjecting a compound (I) or a salt thereof to elimination reaction ofthe amino protective group.

This reaction can be carried out in a similar manner to that of Process1 mentioned in the above, and therefore the reaction mode and reactionconditions [e.g. base, acid, catalyst, solvent, reaction temperature,etc.] of this reaction are to be referred to those as explained inProcess 1.

When the object compound (III) thus obtained is in a salt form, it canbe converted into a free form in a conventional manner (e.g.,neutralization, column chromatography, recrystallization, desaltingresin column chromatography, etc.).

The compounds obtained by the above Processes 1 and 2 can be isolatedand purified by a conventional method such as pulverization,recrystallization, column-chromatography, reprecipitation or the like.

It is to be noted that each of the compounds (I), (II) and (III) mayinclude one or more stereoisomer such as optical isomer(s) andgeometrical isomer(s) due to asymmetric carbon atom(s) and doublebond(s) and all such isomers and mixture thereof are included within thescope of this invention.

The compounds (I), (II) and (III) or a salt thereof include solvatedcompound [e.g., enclosure compound (e.g., hydrate, etc.)].

The compounds (I), (II) and (III) or a salt thereof include both itscrystal form and non-crystal form.

The above invention would make it possible to produce β-alaninederivative in a good yield and/or to obtain a certain stereoisomerthereof which has a specific configuration in a good yield.

The compound (I) or a salt thereof is useful as an intermediate forpreparing the compound (III) or a salt thereof.

So, the production of the compound (I) or a salt thereof in a good yieldis useful as the effective production of the intermediate for thecompound (III) or a salt thereof which is useful as glycoprotainIIb/IIIa antagonist or so.

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail.

Preparation 1

A mixture of 2(S)-benzyloxycarbonylamino-β-alanine (3.0 g) andp-toluenesulfonic acid monohydrate (2.88 g) in benzyl alcohol (15 ml)was heated to 120° C. in the flask fitted with Dean-Stark equipment.After dissolved, toluene (90 ml) was poured into it, and the mixture wasrefluxed for 3.5 hours. The mixture was cooled down to room temperature,and concentrated in vacuo. The residue was resolved in ethyl acetate,washed with saturated aqueous NaHCO₃, water and brine, dried overNa₂SO₄, and evaporated in vacuo. The product was resolved in ethylacetate (50 ml), and cooled to 0° C. To the stirred solution, 4N—HCl inethyl acetate (2.13 ml) was added dropwise at 0° C., then concentratedin vacuo. The oily product was solidified by addition of a mixture ofethyl acetate and isopropyl ether (1:1). The solid was washed withisopropyl ether, and dried in vacuo to give2(S)-benzyloxycarbonylamino-β-alanine benzyl ester hydrochloride (2.75g).

NMR (DMSO-d₆, δ): 3.04-3.29 (2H, m), 4.42-4.53 (1H, m), 5.02-5.17 (4H,m), 7.35 (5H, s), 7.37 (5H, s), 7.95 (1H, d, J=8.4 Hz)

MASS (m/z): 329 (M⁺ free+1)

Preparation 2

To a suspension of 2(S)-benzyloxycarbonylamino-β-alanine (2.0 g) in amixture of dioxane (14 ml), water (7 ml) and 1N aqueous NaOH (6.94 ml)was added di-tert-butyl dicarbonate (1.67 g) at 0° C. After 10 minutes,the temperature was allowed to reach to room temperature, and themixture was stirred for 5 hours. The reaction mixture was evaporated invacuo to remove dioxane, adjusted to pH 3.0 with aqueous 20% KHSO₄, thenextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over Na₂SO₄, and evaporated in vacuo. The resultingsolid was washed with diethyl ether to giveN-tert-butoxycarbonyl-2(S)-benzyloxycarbonylamino-β-alanine (2.28 g).

NMR (CDCl₃, δ): 1.42 (9H, s), 3.44-3.67 (2H, m), 4.34-4.42 (1H, m), 5.13(2H, s), 7.30-7.36 (5H, m)

Preparation 3

To a stirred solution of iodobenzene diacetate (7.26 g) in a mixture ofethyl acetate (44 ml), acetonitrile (44 ml) and water (22 ml) was added2(R)-benzyloxycarbonylamino-succinamic acid (5.0 g) at ambienttemperature. After stirred for 3 hours, the reaction mixture was cooledto 5° C., followed by stirring for 2 hours. Insoluble material wascollected by filtration, washed with ethyl acetate, and dried underreduced pressure to give 2(R)-benzyloxycarbonylamino-β-alanine (4.15 g)as a white solid.

IR (KBr): 3303.5, 3027.7, 2948.6, 1693.2, 1656.5, 1623.8, 1592.9, 1542.8cm⁻¹

NMR (D₂O-TFA, δ): 3.35 (1H, dd, J=13.4 and 8.7 Hz), 3.57 (1H, dd, J=13.4and 5.3 Hz), 4.57 (1H, dd, J=8.7 and 5.3 Hz), 5.16 (2H, s), 7.43 (5H, s)

MASS (m/z): 239 (M+H)⁺

mp: 238° C. (dec.)

[α]_(D) ³¹: 8.6° (c=1.0, 1N NaOH aq.)

Preparation 4

Thionyl chloride (3.22 ml) was added dropwise to methanol (25 ml) at 4°C. under a nitrogen atmosphere. After stirred for 30 minutes, to thereaction mixture was added 2(R)-benzyloxycarbonylamino-β-alanine (3 g),followed by warming to the ambient temperature and stirring overnight.The insoluble material was collected by filtration, washed withdiisopropyl ether, and dried under a reduced pressure to give 2(R)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (3.15 g) asa white solid.

IR (KBr): 3365.2, 3317.0, 2950.5, 2885.0, 2850.3, 1733.7, 1695.1,1594.8, 1537.0 cm⁻¹

NMR (DMSO-d₆, δ): 3.00-3.24 (2H, m), 3.68 (3H, s), 4.39-4.51 (1H, m),5.07 (2H, s), 7.73 (5H, s), 7.94 (1H, d, J=8.2 Hz)

MASS (m/z): 253 (M+H)⁺

mp: 166.0-166.5° C.

[α]_(D) ³⁰: 39.2° (c=1.0, MeOH)

The following compounds [Preparation 5 and 6] were obtained according toa similar manner to that of Preparation 4.

Preparation 5 2(R)-Benzyloxycarbonylamino-β-alanine ethyl esterhydrochloride

IR (KBr): 3322.7, 2863.8, 1727.9, 1695.1, 1596.8, 1540.8 cm⁻¹

NMR (DMSO-d₆, δ): 1.18 (3H, t, J=7.1 Hz), 3.06 (1H, dd, J=13.0 and 9.4Hz), 3.22 (1H, dd, J=13.0 and 4.7 Hz), 4.13 (2H, q, J=7.1 Hz), 4.36-4.48(1H, m), 5.08 (2H, s), 7.37 (5H, s), 7.94 (1H, d, J=8.2 Hz)

MASS (m/z): 267 (M+H)⁺

mp: 141.0-141.5° C.

[α]_(D) ³⁰: 39.9° (c=1.0, MeOH)

Preparation 6 2(S) -Benzyloxycarbonylamino-β-alanine ethyl esterhydrochloride

IR (KBr): 3324.7, 2869.6, 1727.9, 1695.1, 1596.8, 1540.8 cm⁻¹

NMR (DMSO-d₆, δ) 1.18 (3H, t, J=7.1 Hz), 3.06 (1H, dd, J=13.0 and 9.4Hz), 3.22 (1H, dd, J=13.0 and 4.7 Hz), 4.13 (2H, q, J=7.1 Hz), 4.36-4.48(1H, m), 5.08 (2H, s), 7.37 (5H, s), 7.94 (1H, d, J=8.2 Hz)

MASS (m/z): 267 (M+H)⁺

mp: 141.3-141.8° C.

[α]_(D) ³⁰: −39.1° (c=1.0, MeOH)

Preparation 7

To a mixture of(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylicacid (20.0 g), 2(S)-benzyloxycarbonylamino-β-alanine methyl esterhydrochloride (17.2 g) and 1-hydroxybenzotriazole (8.07 g) inN,N-dimethylformamide (200 ml) was added dropwise1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (10.9 ml) at 0° C. Themixture was stirred at 4° C. for 15 hours, then poured into ice water(500 ml), and extracted with ethyl acetate (500 ml×2). The combinedorganic layer was successively washed with water, saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄, and evaporated in vacuo. Theresidue was chromatographed on silica gel eluting with n-hexane-ethylacetate (from 1:1 to ethyl acetate only) to giveN-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alaninemethyl ester (30.5 g) as a colorless oil.

IR (KBr): 3307, 2933, 1724, 1689, 1535, 1434, 1365, 1272, 1243, 1164cm⁻¹

NMR (CDCl₃, δ): 0.97-1.38 (2H, m), 1.46 (9H, s), 1.53-1.67 (7H, m),2.27-2.67 (6H, m), 3.23-3.39 (3H, m), 3.69 (3H, s), 3.54-3.61 (1H, m),4.07-4.14 (4H, m), 4.46-4.51 (1H, m), 5.12 (2H, s), 6.39-6.43 (1H, m),7.32-7.35 (5H, m)

MASS (m/z): 503 (M−Boc+2)⁺

The following compounds [Preparation 8 to 13] were obtained according toa similar manner to that of Preparation 7.

Preparation 8N-[(S)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alaninemethyl ester

NMR (CDCl₃, δ): 0.98-1.84 (11H, m), 1.45 (9H, s), 2.30-2.38 (3H, m),2.59-2.71 (2H, m), 3.32-4.10 (8H, m), 3.76 (3H, s), 4.40-4.50 (1H, m),5.09 (1H, ABq, J=12.3 Hz), 5.13 (1H, ABq, J=12.3 Hz), 7.31-7.37 (5H, m)

MASS (m/z): 625 (M+Na)⁺

Preparation 9N-[(S)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)-propionyl]-3-piperidylcarbonyl]-2(R)-benzyloxycarbonylamino-β-alaninemethyl ester

NMR (CDCl₃, δ) 0.97-1.77 (11H, m), 1.46 (9H, s), 2.35-2.68 (5H, m),3.27-4.21 (8H, m), 3.70 (3H, s), 4.47-4.53 (1H, m), 5.13 (2H, s),7.32-7.38 (5H, m)

MASS (m/z): 625 (M+Na)⁺

Preparation 10N-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alaninebenzyl ester

IR (KBr): 1720, 1710, 1691, 1651 cm⁻¹

NMR (CDCl₃, δ): 0.92-1.15 (2H, m), 1.25-2.67 (15H, m), 1.46 (9H, s),3.12-4.24 (7H, m), 4.46-4.58 (1H, m), 5.00-5.18 (4H, m), 6.40 (1H, d,J=9.3 Hz), 7.23-7.37 (10H, m)

MASS (m/z): 701 (M+Na)⁺

Preparation 11N-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanineethyl ester

IR (KBr): 3309.2, 2977.5, 2935.1, 2859.9, 1726.0, 1689.3, 1652.7, 1535.1cm⁻¹

NMR (DMSO-d₆, δ): 0.89-1.90 (11H, m) , 1.18 (3H, t, J=7.1 Hz), 1.38 (9H,s), 2.20-2.80 (6H, m), 2.80-3.60 (3H, m), 3.65-4.45 (7H, m), 5.04 (2H,s), 7.31 (1H, dd, J=8.0 and 3.8 Hz), 7.95-8.10 (1H, m)

MASS (m/z): 639 (M+Na)⁺

Preparation 12N-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-benzyloxycarbonylamino-β-alaninemethyl ester

IR (KBr): 3309.2, 2935.1, 2859.9, 1726.0, 1689.3, 1535.1 cm⁻¹

NMR (DMSO-d₆, δ): 0.80-1.90 (11H, m), 1.38 (9H, s), 2.20-2.80 (6H, m),2.80-4.00 (6H, m), 3.61 (3H, s), 4.10-4.45 (2H, m), 5.04 (2H, s), 7.36(5H, s), 7.64 (1H, d, J=8.1 Hz), 7.95-8.15 (1H, m)

MASS (m/z): 603 (M+H)⁺, 625 (M+Na)⁺

Preparation 13N-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-benzyloxycarbonylamino-β-alanineethyl ester

IR (KBr): 3309.2, 2977.5, 2935.1, 2859.9, 1726.0, 1689.3, 1654.6, 1533.1cm⁻¹

NMR (DMSO-d₆, δ): 0.80-1.90 (11H, m), 1.17 (3H, t, J=7.1 Hz), 1.38 (9H,s), 2.20-2.80 (6H, m), 2.80-3.50 (3H, m), 3.65-4.45 (7H, m), 5.04 (2H,s), 7.36 (5H, s), 7.62 (1H, d, J=8.1 Hz), 7.95-8.10 (1H, m)

MASS (m/z): 617 (M+H)⁺, 639 (M+Na)⁺

Preparation 14

To a stirred solution of(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylic acid (1.0 g) in tetrahydrofuran (20 ml) was added dropwiseisobutyl chloroformate (356 μl) and 4-methylmorpholine (300 μl) at −15°C. under a nitrogen atmosphere. To an ice cooled solution of2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (783mg) and N-(trimethylsilyl)acetamide (1.78 g) in tetrahydrofuran (30 ml)was added dropwise the above solution with stirring under a nitrogenatmosphere. The reaction mixture was allowed to warm to ambienttemperature, and stirred for 2 hours, which was partitioned betweenethyl acetate and water. The organic layer was separated, washed in turnwith water, aqueous 5% KHSO₄, aqueous 5% NaHCO₃ and brine, and driedover MgSO₄. Evaporation of the solvent gave a residue, which waspurified by silica-gel column chromatography eluting with n-hexane-ethylacetate (from 1:6 to ethyl acetate only) to giveN-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alaninemethyl ester (1.36 g) as a foam, which is the same compound obtained inPreparation 7.

Preparation 15

To a stirred solution of(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylic acid (1.0 g) and N,N-dimethylformamide (210 μl) indichloromethane (10 ml) was added dropwise oxalyl chloride (240 μl) at4° C. under a nitrogen atmosphere. To an ice cooled solution of2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (940mg) and N-(trimethylsilyl)-acetamide (2.85 g) in N,N-dimethylformamide(10 ml) was added dropwise the above solution with stirring under anitrogen atmosphere. The reaction mixture was allowed to warm to ambienttemperature, and stirred for 2 hours, which was partitioned between amixture of ethyl-acetate and n-hexane and water. The organic layer wasseparated, washed in turn with water, aqueous 5% NaHCO₃ solution andbrine, and dried over MgSO₄. Evaporation of the solvent gave a residue,which was purified by silica-gel column chromatography eluting withn-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to giveN-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alaninemethyl ester (0.89 g) as a foam, which is the same compound obtained inPreparation 15.

Preparation 16

To a solution ofN-(t-butoxycarbonyl)-2(S)-benzyloxycarbonylamino-β-alanine (6.15 g) inmethanol (120 ml) was added 10% Pd—C (50% wet, 1.2 g). The mixture wasstirred vigorously, and hydrogen gas was bubbled for 1 hour. Thecatalyst was removed by filtration, and the filtrate was evaporated invacuo. The residue was dissolved in tetrahydrofuran (70 ml) and cooledto 0° C. with ice bath. 1N NaOH (36 ml) was added, then acetic anhydride(3.77 ml) was added dropwise under stirring. The mixture was stirred foradditional 1 hour at 0° C., then the pH of the mixture was adjusted to2.5 with aqueous 20% KHSO₄. The resultant mixture was extracted withethyl acetate-tetrahydrofuran (200 ml-100 ml) twice times. The combinedorganic layer was dried over Na₂SO₄ and evaporated in vacuo. The residuewas recrystallized from diethyl ether to giveN-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine (3.17 g).

IR (KBr): 3370, 3303, 1707, 1689, 1612, 1552, 1513, 1431, 1386, 1369,1309, 1277, 1254, 1173 cm⁻¹

NMR (DMSO-d₆, δ): 1.37 (9H, s), 1.83, (3H, s), 3.21-3.27 (2H, m),4.18-4.28 (1H, m), 6.75-6.85 (1H, m), 7.99 (1H, d, J=7.9 Hz)

MASS (m/z): 245 (M−H)⁻

Preparation 17

To a mixture of N-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine (3.0 g)in dimethylformamide (60 ml) was added NaHCO₃ (2.05 g) at −2° C., and asolution of benzyl bromide in dimethylformamide (60 ml) was added byusing a dropping funnel under stirring. The mixture was stirredovernight around 26° C., then poured into a mixture of ice-water (300ml) and hexane-ethyl acetate (8:2, 500 ml). After the organic layer wasseparated, the aqueous layer was extracted again with hexane-ethylacetate (8:2, 300 ml). The combined organic layer was washed with water(300 ml×2), brine (300 ml) and dried over Na₂SO₄, and evaporated invacuo. The residue was purified by silica gel chromatography elutingwith hexane-ethyl acetate (8:2) to giveN-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine benzyl ester (3.68 g).

IR (KBr): 3361, 3324, 1739, 1687, 1650, 1536, 1456, 1440, 1392, 1369,1346, 1319, 1278, 1251, 1203, 1174 cm⁻¹

NMR (CDCl₃, δ): 1.42 (9H, s), 2.03 (3H, s), 3.51-3.56 (2H, m), 4.60-4.68(1H, m), 4.80 (1H, br), 5.18 (2H, s), 7.36 (5H, singlet like)

MASS (m/z): 237 (M−Boc+2H)⁺

Preparation 18

To an ice-cooled solution ofN-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine benzyl ester (3.44 g) inethyl acetate (35 ml) was added 4N HCl in ethyl acetate (25.5 ml). Themixture was stirred for 2.5 hours at an ambient temperature, then thesolvent was decanted. The residue was washed with diethyl ether severaltimes, and dried in vacuo to give 2(S)-acetylamino-β-alanine benzylester hydrochloride (2.31 g) as a white powder.

IR (KBr): 3413, 3245, 1739, 1660, 1612, 1537, 1500, 1454, 1377, 1307,1220, 1166 cm⁻¹

NMR (DMSO-d₆, δ) 1.89 (3H, s), 3.03-3.28 (2H, m), 4.54-4.65 (1H, m),5.15 (2H, s), 7.33-7.39 (5H, m), 8.25 (3H, br), 8.67 (1H, d, J=7.7 Hz)

MASS (m/z): 237 (M+H)⁺

Preparation 19

To a solution of 2(S)-acetylamino-β-alanine benzyl ester hydrochloride(1.86 g), N-(t-butoxycarbonyl)-3(R)-nipecotic acid (1.64 g) and1-hydroxybenzotriazole (0.97 g) in dimethylformamide (25 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.31 ml) at 0° C. Themixture was stirred for 2 hours at room temperature, then poured intoice water-ethyl acetate. The separated organic layer was washed withwater, aqueous saturated NaHCO₃, brine, dried over Na₂SO₄, andevaporated in vacuo. The residue was purified by silica gelchromatography eluting with CHCl₃—MeOH (95:5) to giveN-[(R)-1-(t-butoxycarbonyl)-3-piperidyl-carbonyl]-2(S)-acetylamino-β-alaninebenzyl ester (2.84 g).

IR (Film): 3300, 2938, 1741, 1666, 1648, 1552, 1533, 1469, 1434, 1367,1301, 1265, 1241, 1151 cm⁻¹

NMR (CDCl₃, δ): 1.46 (9H, S), 1.55-1.77 (4H, m), 2.04 (3H, s), 2.10-2.22(1H, br), 3.10 (2H, br), 3.79 (2H, br), 3.64-3.67 (2H, m), 3.79-3.85(1H, br), 4.62-4.71 (1H, m), 5.18 and 5.30 (total 2H, s), 7.26-7.40 (5H,m)

MASS (m/z): 348 (M−Boc+2H)⁺

Preparation 20

To an ice-cooled solution ofN-[(R)-1-(t-butoxycarbonyl)-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl ester (2.7 g) was added 4N HCl in ethylacetate (25.5 ml). The mixture was stirred for 2.5 hours at an ambienttemperature, then the solvent was decanted. The residue was washed withdiethyl ether several times, and dried in vacuo to giveN-[(R)-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl esterhydrochloride (2.29 g) as a white powder.

IR (Film): 3267, 3064, 2958, 1741, 1656, 1543, 1452, 1376 cm⁻¹

NMR (DMSO-d₆, δ): 1.45-1.87 (4H, m), 1.91 (3H, s), 2.62-2.85 (3H, m),3.09-3.46 (4H, m), 4.38-4.42 (1H, m), 5.01-5.14 (2H, m), 7.37-7.39 (5H,m), 8.37-8.41 (2H, m), 8.78 (1H, br), 8.98 (1H, br)

MASS (m/z): 348 (M+H)⁺

EXAMPLE 1

A mixture ofN-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxy-carbonylamino-β-alaninemethyl ester (20 g) and 10% Pd on carbon (50% wet) (5 g) in methanol(500 ml) was stirred vigorously under a hydrogen atmosphere (1 atm) atroom temperature. After 2 hours, the insolved material was removed byfiltration, and the filtrate was concentrated in vacuo. The residue wasdissolved in tetrahydrofuran (200 ml), and cooled to 0° C. 1N aqueousLiOH (116 ml) solution was added to the solution within 15 minutes at0-3° C. After the mixture was stirred for 45 minutes at 0° C., aceticanhydride (6.89 ml) was added to the mixture within 15 minutes at 0-4°C. The mixture was stirred for 30 minutes at 0° C., then diethyl ether(150 ml) was added. The aqueous layer was separated, and the pH of itwas adjusted to 2.5 with aqueous 20% KHSO₄ , then extracted with ethylacetate. The extract was dried over Na₂SO₄, and concentrated in vacuo togiveN-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine(16.3 g) as a colorless oil.

IR (KBr): 3303, 2931, 1732, 1664, 1544, 1475, 1436 cm⁻¹

NMR (CDCl₃, δ) 1.07-1.25 (2H, m), 1.44 (9H, s), 1.51-1.76 (7H, m),1.89-1.95 (2H, m), 2.05 (3H, s), 2.35-2.39 (3H, m), 2.61-2.73 (2H, m),3.24-3.35 (2H, m), 3.56-3.84 (3H, m), 4.06-4.20 (3H, m), 4.33-4.60 (1H,m), 7.43-7.51 (2H, m)

MASS (m/z): 519 (M+Na)⁺

EXAMPLE 2

N-[(S)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alaninewas obtained fromN-[(S)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester according to a similarmanner to that of Example 1.

IR (KBr): 3311, 1738, 1678, 1668, 1655 cm⁻¹

NMR (CDCl₃, δ): 1.00-2.11 (11H, m), 1.45 (9H, s), 2.03 (3H, s),2.33-2.40 (3H, m), 2.60-2.73 (2H, m), 3.06-3.26 (2H, m), 3.48-4.59 (9H,m), 7.52-7.58 (1H, m), 7.70 (1H, d, J=7.0 Hz)

MASS (m/z): 497 (M⁺+1)

EXAMPLE 3

N-[(S)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-acetylamino-β-alaninewas obtained fromN-[(S)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-benzyloxycarbonylamino-β-alaninemethyl ester according to a similar manner to that of Example 1.

IR (KBr): 3311, 1738, 1720, 1676, 1668, 1655 cm⁻¹

NMR (CDCl₃, δ): 1.01-2.06 (11H, m), 1.45 (9H, s), 2.06 (3H, s),2.12-2.40 (3H, m), 2.61-2.73 (2H, m), 3.09-3.86 (6H, m), 4.00-4.64 (3H,m), 7.39-7.43 (1H, m)

MASS (m/z): 497 (M⁺+1)

EXAMPLE 4

N-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)-propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alaninewas obtained fromN-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanineethyl ester according to a similar manner to that of Example 1, and wasthe same compound obtained in Example 1.

EXAMPLE 5

N-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-acetylamino-β-alaninewas obtained fromN-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-benzyloxycarbonylamino-β-alaninemethyl ester according to a similar manner to that of Example 1.

IR (KBr): 3305.4, 2975.6, 2933.2, 2861.8, 1733.7, 1660.4, 1544.7 cm⁻¹

NMR (DMSO-d₆, δ): 0.90-1.95 (11H, m), 1.38 (9H, s), 1.84 (3H, s),2.20-2.80 (5H, m), 2.80-3.60 (4H, m), 3.70-4.00 (3H, m), 4.20-4.45 (2H,m), 7.90-8.10 (2H, m)

MASS (m/z): 495 (M−H)⁻

EXAMPLE 6

N-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-acetylamino-β-alaninewas obtained fromN-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-benzyloxycarbonylamino-β-alanineethyl ester according to a similar manner to that of Example 1, and wasthe same compound obtained in Example 5.

EXAMPLE 7

A mixture ofN-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxy-carbonylamino-β-alaninebenzyl ester (540 ml), acetic acid (0.046 ml) and 10% Pd—C (108 mg) inmethanol (11 ml) was hydrogenated at atmospheric pressure for 1.5 hours.After the catalyst was removed by filtration, the filtrate wasconcentrated in vacuo. The residue was resolved in a mixture of dioxane(4.8 ml) and 1N aqueous NaOH (2.46 ml), cooled down to 0° C., and addedacetic anhydride (0.12 ml) in dropwise. After 5 minutes, the temperaturewas allowed to reach to room temperature. Water and ethyl acetate werepoured into the reaction mixture, and the separated aqueous layer wasadjusted to pH 3.0 with aqueous 5% KHSO₄, extracted with ethyl acetatethree times. The combined organic layer was washed with brine, driedover Na₂SO₄ and evaporated in vacuo to giveN-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine(332 mg), which was the same compound obtained in Example 1.

EXAMPLE 8

To a solution ofN-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine(14.9 g) in ethyl acetate (150 ml) was added dropwise 4N HCl in ethylacetate (74.8 ml) for 10 minutes at 0° C. After the mixture was stirredfor 1 hour and 20 minutes, a white solid was collected by filtration,and dried in vacuo. The powder was dissolved in water (150 ml), and thesolution was neutralized to pH 6.5 with saturated aqueous NaHCO₃. Thesolution was concentrated to about 100 ml, then applied to ODS column(Disogel-120SP®, 1 l), and eluted with 4-6% CH₃CN/water. The eluent wasconcentrated in vacuo, and the residue was dissolved 0.5% aqueousethanol (200 ml). After the mixture was stirred at room temperatureovernight, the resultant solid was collected by filtration, and dried invacuo to giveN-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2-(S)-acetylamino-β-alanine(6.85 g) as a white crystal.

IR (KBr): 3430, 2942, 2861, 1630, 1610, 1475, 1444, 1394 cm⁻¹

NMR (D₂O, δ): 1.37-1.94 (11H, m), 2.03 (3H, s), 2.35-2.54 (3H, m),2.85-3.06 (3H, m), 3.21-3.47 (4H, m), 3.63-3.74 (1H, m), 3.89-3.92 (1H,m), 4.15-4.31 (1H, m), 4.35-4.41 (1H, m)

MASS (m/z): 397 (M⁺+1)

mp: 233° C.

[α]_(D) ²⁶: −11.8° (c=1.0, MeOH)

Anal Calcd. for C₁₉H₃₂N₄O₅.2H₂O: C 52.76, H 8.39, N 12.95 Found C 52.42,H 8.92, N 12.84

EXAMPLE 9

N-[(S)-1-[3-(4-Piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alaninewas obtained fromN-[(S)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanineaccording to a similar manner to that of Example 8.

IR (KBr): 2947, 2858, 1666, 1628, 1599 cm⁻¹

NMR (D₂O, δ): 1.30-2.30 (11H, m), 2.03 (3H, s), 2.35-2.55 (3H, m),2.81-3.05 (3H, m), 3.12-3.52 (4H, m), 3.60-3.70 (1H, m), 3.85-3.97 (1H,m), 4.13-4.30 (1H, m), 4.35-4.42 (1H, m)

MASS (m/z): 397 (M⁺+1)

mp: 131.2-131.7° C.

[α]_(D) ²⁷: +46.2° (c=1.0, MeOH)

Anal Calcd. for C₁₉H₃₂N₄O₅.2.5H₂O: C 51.69, H 8.45, N 12.69 Found: C51.25, H 8.64, N 12.53

EXAMPLE 10

N-[(S)-1-[3-(4-Piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-acetylamino-β-alaninewas obtained fromN-[(S)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-acetylamino-β-alanineaccording to a similar manner to that of Example 8.

IR (KBr): 3421, 2941, 2860, 1645, 1637, 1630, 1618 cm⁻¹

NMR (D₂O, δ): 1.37-1.95 (11H, m), 2.03 (3H, s), 2.36-2.54 (3H, m),2.80-3.01 (3H, m), 3.17-3.48 (4H, m), 3.63-3.75 (1H, m), 3.81-3.95 (1H,m), 4.16-4.32 (1H, m), 4.34-4.41 (1H, m)

MASS (m/z): 397 (M⁺+1)

mp: >220° C.

[α]_(D) ²⁶: +12.2° (c=1.0, MeOH)

Anal Calcd. for C₁₉H₃₂N₄O₅.2H₂O: C 52.76, H 8.39, N 12.95 Found: C52.87, H 8.99, N 12.90

EXAMPLE 11

N-[(R)-1-[3-(4-Piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-acetylamino-β-alaninewas obtained fromN-[(R)-1-[3-(1-tert-Butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(R)-acetylamino-β-alanineaccording to a similar manner to that of Example 8.

IR (KBr): 3463.5, 3251.4, 3089.4, 1666.2, 1627.6, 1598.7, 1542.8 cm⁻¹

NMR (D₂O, δ): 1.30-2.10 (11H, m), 2.03 (3H, s), 2.30-2.65 (3H, m),2.80-3.70 (8H, m), 3.80-4.45 (3H, m)

MASS (m/z): 397 (M+H)⁺, 419 (M+Na)⁺

mp: 124.0-124.5° C. (10% Isopropanol aq.)

[α]_(D) ²⁹: 45.9° (c=1.0, MeOH)

Anal Calcd. for C₁₉H₃₂N₄O₅.3H₂O: C 50.65, H 8.50, N 12.44 Found: C50.88, H 8.57, N 12.49

EXAMPLE 12

To a solution of N-[(R)-3-piperidylcarbonyl]-2(S)-acetylamino-β-alaninebenzyl ester hydrochloride (231 mg), 3-(4-pyridyl)-2-propenoic acid (82mg) and 1-hydroxybenzotriazole (81 mg) in dimethylformamide (2 ml) wasadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.11 ml) at 0° C.The mixture was stirred for 2 hours at room temperature, then pouredinto ice water-ethyl acetate. The separated organic layer was washedwith water, aqueous saturated NaHCO₃, brine, dried over Na₂SO₄, andevaporated in vacuo. The residue was purified by silica gelchromatography eluting with CHCl₃—MeOH (96:4) to giveN-[(R)-1-[3-(4-pyridyl)-2-propenoyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alaninebenzyl ester (263 mg) as a colorless oil.

IR (Film): 3376, 3334, 2937, 1739, 1650, 1599, 1550, 1455, 1394, 1301,1224 cm⁻¹

NMR (CDCl₃, δ): 1.58-1.87 (4H, m), 2.02 and 2.06 (total 3H, s),2.15-2.25 (1H, m), 2.40-2.50 (1H, m), 3.43-3.76 (4H, m), 3.91-4.00 (2H,m), 4.70-4.78 (1H, m), 5.05-5.19 (2H, m), 7.08 (1H, d, J=15.6 Hz),7.32-7.38 (7H, m), 7.54 (1H, d, J=15.6 Hz), 8.62-8.65 (2H, m)

MASS (m/z): 479 (M+H)⁺

EXAMPLE 13

A mixture ofN-[(R)-1-[3-(4-pyridyl)-2-propenoyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alaninebenzyl ester (233 mg), PtO₂ (60 mg) in ethanol (10 ml), 4N HCl in ethylacetate (121 μl) and PtO₂ (50% wet, 1.2 g) was stirred vigorously underhydrogen (1 atm) atmosphere. After 3.5 hours, the catalyst was removedby filtration, and the filtrate was evaporated in vacuo. The residue wasdissolved in water (10 ml). The solution was adjusted to pH 6.5 withaqueous NaHCO₃, then evaporated in vacuo. The residue was purified byODS-chromatography (Disogel SP-120®) eluting with 4% CH₃CN/water. Theeluent was concentrated in vacuo and freeze-dried to giveN-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine(154 mg) as a white powder, which is the compound obtained in Example 8.

Preparation 21

A mixture of 3-piperidinecarboxylic acid ethyl ester (50 g) andL-tartaric acid (48 g) in isopropyl alcohol (1000 ml) and water (5 ml)was stirred at 40° C. The solution was cooled and stirred at roomtemperature.

The precipitate was filtered, washed with isopropyl alcohol (50 ml) anddried in vacuo to give (R)-3-piperidinecarboxylic acid ethyl esterL-tartaric acid salt as white solid. The solid was resolved withisopropyl alcohol (726 ml) and water (36 ml) at 65° C. The solution wascooled and stirred at room temperature. The precipitate was filtered anddried to give pure (R)-3-piperidinecarboxylic acid ethyl esterL-tartaric acid salt (30.3 g).

To a solution of (R)-3-piperidinecarboxylic acid ethyl ester L-tartaricacid salt (30.3 g) in ethyl acetate (300 ml) and water (60 ml), 12%aqueous sodium hydroxide was added to adjust pH to 13. Aqueous layer wasextracted with ethyl acetate (60 ml) two times and combined organiclayer was dried with sodium sulfate (8 g). Organic layer wasconcentrated in vacuo to give (R)-3-piperidinecarboxylic acid ethylester (15.3 g).

IR. (oil): 2939, 2856, 1731, 1446, 1373 cm−1

NMR(DMSO-d₆, δ):1.66 (3H, t), 1.27-1.58 (3H, m), 1.81-1.89(1H, m),2.26-2.41(2H, m), 2.46(1H, m), 2.57(1H, m), 2.66(1H, d), 2.98(1H, d),4.03(2H, q)

MASS (m/z): 157

Preparation 22

To a mixture of malonic acid (12 g), pyridine (7.6 g) in ethanol(41 ml)was added dropwise 4-pyridinecarbaldehyde (10.3 g) at 40° C. The mixturewas stirred at 80° C. for 5 hours, then cooled to room temperature. Theprecipitate was filtered washed with ethanol and dried in vacuo to give3-(4-pyridyl)-2-propenoic acid (10.4 g)

IR(KBr): 3054, 2359, 1700, 1645, 1607,1555, 1415, 1341, 1311 cm⁻¹

NMR(DMSO-d₆, δ): 3.33(1H, s), 6.78(1H, d), 7.52(1H, d), 7.66(2H, d),8.62(2H, d)

MASS (m/z): 150 (M+1)

Preparation 23

A mixture of 3-(4-pyridyl)-2-propenoic acid (10 g) , 10% Pd—C (1 g) inacetic acid (40 ml) was hydrogenated (3.0 kg/cm²) at 65° C. for 8 hours.After the catalyst was removed by filtration, the filtrate wasconcentrated in vacuo. The residue was resolved in toluene (30 ml) andconcentrated in vacuo. The residue was resolved in water (30 ml) andtetrahydrofuran (50 ml), cooled to 0° C., and triethylamine (33 g) wasadded dropwise at 5° C. Di-t-butyl dicarbonate (18.3 g) was added to themixture at 20° C. and stirred overnight. PH was adjusted to 7 with HCl,organic layer was washed with 10% aqueous citric acid (40 ml), 5%aqueous sodium chloride (40 ml), dried over magnesium sulfate (5 g) andconcentrated in vacuo. The residue was resolved in toluene (20 ml),concentrated in vacuo to 25 ml. The mixture was stirred at 40° C. for 3hours, n-heptane (20 ml) was added to the mixture and stirred at 0° C.overnight. The precipitate was separated and dried to give3-(1-tert-butoxycarbonyl-4-piperidyl)propionic acid as white solid (12.8g).

IR(KBr): 3300, 2937, 1734, 1670, 1479, 1455, 1285, 1173 cm⁻¹

NMR(DMSO-d₆, δ) 0.9-1.0(2H, m), 1.38(9H, s), 1.3-1.5(1H, m), 1.6(2H, m),2.22(2H, t), 2.64(2H, m), 3.30(1H, s), 3.9(2H, m)

MASS(m/z): 158(M+1−BOC)

Preparation 24

To a mixture of (R)-3-piperidinecarboxylic acid ethyl ester (7.7 g),3-(1-tert-butoxycarbonyl-4-piperidyl)propionic acid (12.5 g),1-hydroxybenztriazole (6.6 g) in dimethylformamide was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (7.6 g) at 5° C. Themixture was stirred at 25° C. overnight. Ethyl acetate (96 ml) and water(94 ml) was added to the mixture. Organic layer was separated andaqueous layer was extracted with ethyl acetate (94 ml) two times.Combined organic layer was washed with 9% aqueous sodium bicarbonate (63ml), water (63 ml), 20% aqueous sodium chloride (63 ml) and concentratedin vacuo.

The residue was resolved in methanol (164 ml) and was added to thesolution of lithium hydroxide (3.9 g) in water (110 ml) at 5° C. Themixture was stirred overnight, then pH was adjusted to 2.6 with3N-hydrochloric acid and stirred overnight at 35° C.

After cooling to 0° C., the precipitate was filtered, washed with 30%aqueous methanol and dried in vacuo to give(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylicacid (13.8 g) as white solid.

IR(KBr): 2931, 2885, 1732, 1688, 1628, 1607, 1471, 1236, 1166 cm⁻¹

NMR(DMSO-d₆, δ): 0.92-1.06(2H, m), 1.28-1.51(3H, m), 1.38(9H, s),1.51-1.78(4H, m), 1.8-2.0(1H, m), 2.2-2.4(4H, m), 2.5-2.7(2H, m),2.9-3.1(1H, m), 3.2-3.8(1H, m), 3.7-4.5(4H, m)

MASS(m/z): 269(M+1−BOC)

EXAMPLE 14

N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine(20.0 g) was treated under atmosphere RH 50%, 25° C. for 40 hours togiveN-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alaninetrihydrate (21.6 g), whose stability against humidity was very good.

IR(KBr): 2726, 2606, 1658, 1616, 1539, 1328, 1304, 1268, 1232, 1223 cm⁻¹

X-Ray powder diffraction: (2 θ) 11.26, 13.39, 18.60, 20.43, 21,16, 22.05

What is claimed is:
 1. The compound N-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidyl-carbonyl]-2(S)-acetylamino-β-alanine trihydrate or a trihydrate salt thereof.
 2. The N-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidyl-carbonyl]-2(S)-acetylamino-β-alanine trihydrate of claim 1, which has the following structure:


3. The compound of claim 1 in the form of a salt.
 4. The compound of claim 1 in the form of a metal salt.
 5. The compound of claim 1 in the form of an alkaline earth metal salt.
 6. The compound of claim 1 in the form of an ammonium or organic base salt.
 7. The compound of claim 1 in the form of an organic acid addition salt.
 8. The compound of claim 1 in the form of a salt with an amino acid.
 9. A stereoisomer of the compound of claim
 1. 10. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
 11. A method for antagonizing glycoprotein IIb/IIIa activity comprising administering an effective amount of the compound of claim 1 to a subject in need thereof.
 12. A method for inhibiting platelet aggregation comprising administering an effective amount of the compound of claim 1 to a subject in need thereof.
 13. A method for inhibiting the binding of fibrinogen to blood platelets comprising administering an effective amount of the compound of claim 1 to a subject in need thereof. 